OPRM1 and Reward Sensitivity In humans, a functional variant in the OPRM1 gene (OPRM1 A118G) alters the receptors affinity. A functionally similar variant (OPRM1 C77G) is present in the rhesus macaque. We have found that OPRM1 C77G increases sensitivity to natural rewards, as reflected in increased measures of infant attachment in response to repeated mother-infant separation (Barr et al, 2008). We have examined the effects of the OPRM1 C77G variant and find that, similar to the human variant, it influences alcohol-induced stimulation, a marker of euphorogenic alcohol actions, and also increases alcohol preference and consumption (Barr et al, 2007). As genetic variation that influences endogenous opioid response could also potentially impact the incentive-motivational aspects of novelty seeking, we wanted to investigate whether OPRM1 genotype would also influence response to novelty in rhesus macaques. We have observed infants behaviors in an unfamiliar environment and adults reactions to an unfamiliar conspecific and then examined whether individual behavioral responses varied as a function of OPRM1 C77G genotype. We found that males carrying the OPRM1 77G allele are quicker to explore a novel environment and more likely to approach an unfamiliar conspecific, traits that could be adaptive in certain environmental contexts (Lindell et al, in prep). Our findings suggest that variation at the OPRM1 locus may be associated with differences in novelty seeking in human subjects. Recently, some of our macaque findings have been translated to humans. We found that OPRM1 A118G genotype interacted with parent unavailability: as a function of parental problems (ie, significant mental health problems, substance abuse, criminal arrest), G allele carriers reported more enjoyment of parent-child interactions and lower levels of separation anxiety. The G allele also predicted increased levels of early alcohol use and alcohol-related problems, independent of parental problems. These findings replicate our findings in the rhesus macaque and suggest a role for OPRM1 genotype in both the genetic architecture of social attachment and problematic alcohol use in humans (Copeland et al, submitted). Early Life Stress in Primates and GxE Interactions Traumatic experiences in early childhood are associated with increased risk of developing stress-related disorders, which are linked to structural brain abnormalities. We have been working to identify structural abnormalities in the primate brain that may predict increased risk of stress-related neuropsychiatric disorders in humans. We found that macaques exposed to early stress in the form of peer rearing had an enlarged vermis, dorsomedial prefrontal cortex, and dorsal anterior cingulate cortex. This study demonstrated that peer-rearing during infancy induces enlargement in stress-sensitive brain regions. These changes may be a structural phenotype for increased risk of stress-related neuropsychiatric disorders in human beings (Spinelli et al, 2009). Different strategies for coping with environmental stressors have evolved in males and females, and these differences may underlie the differential prevalence of certain types of psychopathology in the two sexes. We have investigated the possibility of sex-specific gene-environment interactions in a nonhuman primate model of response to social threat (Schwandt et al, in review). We found levels of high risk aggression to be increased in males carrying the HTTLPR s allele that were exposed to early adversity in the form of peer rearing. Our findings support those from recent studies in humans suggesting that males are more vulnerable to externalizing or aggression-related disorders. The results highlight the importance of interactions that exist among behavior, genes, and the environment and suggest that sex differences in vulnerability to psychopathology may be grounded in our evolutionary history. Development of Primate Models with Predictive Validity for Evaluating Treatment Response In rodents, periods of alcohol deprivation have been shown to induce high levels of consumption and dependence. We have instituted the use of an every-other-day (EOD) paradigm to induce escalated alcohol intake in macaques, with the goal of developing a model that has predictive validity for evaluating compounds being developed to treat alcoholism. Using this paradigm, we were able to induce levels of consumption that were 70% higher than those observed among animals given every day access. In subjects tested under this paradigm, BECs were in the 100-200 mg% range, a level that has been demonstrated to be required for transitioning to dependence in rodents. We also demonstrated that by using an intermittent access schedule, within 9 weeks of testing, animals significantly increased the duration of time during which they consumed alcohol. In the morning, EOD subjects showed increased alcohol intake within weeks, but levels were no different than those observed in controls by the afternoon/evening. By 9 weeks of access, these subjects showed significant increases in evening consumption relative to baseline levels and to controls assessed during the same phase. This suggests that, with increased duration of intermittent access to alcohol, rhesus macaques will not only increase the amount that they drink upon reinstatement, but are more persistent in their alcohol seeking. Relevance to Treatment for Alcohol Dependence- Individual Differences in Treatment Response Studies performed in rodents have shown that the transition to alcohol dependence depends on alterations in the CRH and NPY systems. We have shown that functional genetic variants that impact these systems predict alcohol consumption in macaques (Barr et al, 2009;Lindell et al, in press). Because there may also be individual differences in the degrees to which these systems are dysregulated following intermittent drinking, we tested whether cerebrospinal fluid (CSF) levels of CRH predicted response to the CRHR1 antagonist, antalarmin. Our data show that intermittent access to alcohol induces escalated alcohol consumption, but does not necessarily do so through recruitment of the CRH system. We also show that, although CRH antagonism does not reduce consumption among all subjects, that it is effective in individuals with high CSF levels of CRH following prolonged periods of alcohol consumption (Schwandt et al, in prep). Our results suggest that treatment with CRH receptor antagonists might be more effective among individuals in whom increased CRH system functioning drives alcohol drinking. In humans, the OPRM1 A118G polymorphism has been associated with alcohol-induced euphoria and naltrexone response, though results have been mixed. We have examined the effects of the OPRM1 C77G variant and find that, similar to the human variant, it influences alcohol-induced stimulation, a marker of euphorogenic alcohol actions, and increases alcohol preference and consumption (Barr et al, 2007). More recently, we demonstratred that it impacts naltrexone response (Barr et al, 2009). We found opposite directionality of the naltrexone effect in 77G carriers and subjects homozygous for the major 77C allele. While alcohol preference was markedly suppressed in 77G carriers, we observed increased preference in 77C homozygous individuals. This pattern parallels a human study that examined family history of alcoholism as a moderator of naltrexone response under laboratory conditions, and found suppression of self-administration in family history positive subjects, but significantly increased self-administration following naltrexone treatment in family history negative participants. This provides evidence in a controlled animal study that OPRM1 genotype is likely a predictor of naltrexone response in human patient populations.